- Clinical science
Anticoagulants are used for treating and preventing embolic events. The most common oral anticoagulatory agents are vitamin K antagonists such as warfarin (Coumadin®) and phenprocoumon. Non-vitamin K antagonist oral anticoagulants (NOACs) like dabigatran and rivaroxaban have also gained popularity in recent years. Vitamin K antagonists inhibit the enzyme vitamin K epoxide reductase, thereby blocking hepatic synthesis of the active, reduced form of vitamin K (needed for carboxylation of coagulation factors II, VII, IX, and X, protein C, protein S). This effect can last for several days, which complicates exact dosing and makes regular monitoring necessary. Vitamin K antagonists are also metabolized by C-P450 (CYP) enzymes and therefore interact with a broad range of foods and drugs. NOACs act selectively via inhibition of thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban). Because of their comparatively short half-life and fewer interactions, NOACs are easier to control and administer than warfarin and do not require regular monitoring to ensure their efficacy and safety. There are no established tests for monitoring overdosing since the usual coagulation studies (aPTT, factor Xa activity) can yield false results. For all substances, it is important to consider the dose-dependent risk of bleeding, especially when combining different substances that affect hemostasis (e.g., aspirin, clopidogrel, ticagrelor).
Overview of commonly used oral anticoagulants
|Substances||Mechanism of action|
|Vitamin K antagonists (coumarins)|
|Non-vitamin K antagonist oral anticoagulants|
|Direct oral thrombin inhibitors|| || |
|Direct oral factor Xa inhibitors|| |
|General notes regarding oral anticoagulation|
|Indications for all oral anticoagulants|
Expected laboratory changes
The most important side effect of all oral anticoagulants is a dose-dependent increase in bleeding risk!
Dose-dependent increased risk of bleeding
- Severe cases of hemorrhage are usually retroperitoneal, intracranial, or gastrointestinal.
- Countermeasures in case of bleeding
Warfarin-induced skin necrosis
- Warfarin inhibits all vitamin K-dependent coagulation factors
- Presentation: painful purpura, hemorrhagic blisters, and large areas of necrosis; mostly affects subcutaneous adipose tissue
- Therapy: Protein C concentrate; surgical debridement and grafting in therapy-refractory cases
- Prevention: temporary with therapyheparin for immediate anticoagulation until warfarin has started to act
Direct factor Xa inhibitors and direct thrombin inhibitors
Dose-dependent increased risk of bleeding
- Interventional steps to stop the bleeding
- If life-threatening bleeding occurs, administer PCC
- Antifibrinolytic agents (e.g., tranexamic acid)
- Oral activated charcoal; reduces absorption if anticoagulants were ingested in the past couple of hours.
- Apixaban and rivaroxaban: andexanet alfa (recombinant modified factor Xa protein)
- Dabigatran: idarucizumab (monoclonal antibody)
We list the most important adverse effects. The selection is not exhaustive.
|Direct thrombin inhibitors|| |
|Direct factor Xa inhibitors|
- Coagulopathies; hepatic dysfunction with impaired hepatic production of coagulation factors
- Acute bleeding
- Suspected vascular lesions, increased risk of severe bleeding
- Severe renal insufficiency
- Concurrent administration of several anticoagulants
- Pregnancy and breastfeeding
- Specific contraindications
We list the most important contraindications. The selection is not exhaustive.
- Decrease of anticoagulant effect
Increase of anticoagulant effect
- Several antidepressants and antibiotics, PPIs, amiodarone, grapefruit: impair metabolic breakdown via inhibition of cytochrome P450
- Acetaminophen: metabolite of acetaminophen interrupts vitamin K cycle via inhibition of vitamin K-dependent carboxylase
- Sulfonamides, sulfonylureas: competitively block or displace warfarin at plasma protein binding sites
- Damage to gut flora (e.g., antibiotic therapy): impaired bacterial vitamin K synthesis
P450 inducers: ↓ warfarin levels (Chronic Alcoholics Steal Phen-Phen and Never Refuse Greasy Carbs): C - Chronic alcohol use, S - St. John's wort, P - Phenytoin, P - Phenobarbital, N - Nevirapine, R - Rifampin, G - Griseofulvin, C - Carbamazepine
P450 inhibitors can be remembered with “sickfaces.com group”: S - Sulfonamides, I - Isoniazid, C - Cimetidine, K - Ketoconazole, F - Fluconazole , A - Alcohol (binge drinking), C - Ciprofloxacin, E - Erythromycin, S - Sodium valproate, C - Chloramphenicol, O - Omeprazole, M - Metronidazole, G - Grapefruit juice
Preoperative bridging therapy
- Stop coumarin administration 5–6 days before surgery.
- Administer a therapeutic dose of the bridging drug 3 days before surgery; , with the last dose administered 24 hours before the procedure.
- Resume the bridging drug and warfarin after surgery; ; administer the bridging drug for 4–6 days post-surgery.